Delta8(14), 22-3-acetoxy-11-keto-ergostadiene and process for the preparation thereof



This invention is concerned generally with steroid compounds having anoxygen atom attached to the carbon atom in the ll-position of themolecule and with processes for preparing these ll-oxygenated steroidcompounds. More particularly, it relates to a novel process forconverting epoxides of A" -cyclopentanopoly- Compound 1 Compound 2hydrophenanthrene compounds to the corresponding A-l1-keto-cyclophentanopolyhydrophenanthrene compounds, and to theintermediate compounds thus obtained. The A-11-keto-cyclophentanopolyhydrophenanthrene compounds prepared inaccordance with our novel procedure are valuable as intermediates in thesynthesis of other steriod compounds having an oxygen atom attached tothe ll-carbon atom, such as the adrenal hormones, corticosterone,cortisone and Compound F.

This application is a continuation-impart of copending applicationsSerial No. 262,647, filed December 20, 1951, now abandoned, and SerialNo. 621,985, filed November 14, 1956, now abondoned, the latter of whichis a division of application Serial No. 263,476, filed December 26,1951, now Patent No. 2,798,082.

The A -1l keto-cyclopentanopolyhydrophenanthrene compounds, subject ofthe present invention have at rings B and C the following chemicalstructure:

319925642? Patented June 4, 1963 spending A -7,11-dihalo-cyclopentanopolyhydrophenanthrene compound (Compound 3); thelatter compound is reacted with an aqueous solution of metal saltcharacterized as having a cation which forms water-insoluble halides andan anion which is non-reactive with steriod compounds, thereby producingthe corresponding ll-ketocyclopentanopolyhydrophenanthrene compoundhaving a double bond connecting the carbon atom in the 8-position with acarbon atom adjacent thereto and gamma with respect to the ll-ketosubstituent (Compound 4). This compound is then treated with a base toform the corresponding A 1l-keto-cyclopentanopolyhydrophenanthrenecompound (Compound 5).

The reactions indicated hereinabove may be chemically represented,insofar as rings B and C are concerned, as

follows r O l Compound 5 Compound 4 wherein X represents halogen.

The epoxides of A -cyclopentanopolyhydrophenanthrene compounds which weordinarily empoly as starting materials in carrying out the presentlyinvented process are those having a sterol side chain attached to thecarbon atom in the 17-position of the molecule such as ergosterylD-acetate epoxide, A' -ergostadiene epoxide, A -3-acyloxy-ergostadieneepoxide, A cholestene epoxide, A -3-acy1oxy-cholestene epoxide, A-3-acetoXy-ch0lesteneepoxide, A -3-acyloXy-stigmastadiene epoxide, A-B-acetoXy-Stigmastadiene-epoxide, a bile acid side chain attached tothe 17-carbon atom such as A -3-acyloxy-cholenic acid epoxide, adegraded bile acid side chain attached to the 17-carbon atom such as A-3-acyloxy-bisnorallocholenic acid epoxide, A -3acetoxy-bisnorallocholenic acid epoxide, a 17 acetyl substituent such asA' -3- acyloxy-ZO-keto-allopregnene epoxide, A -3-acetoxy-20-keto-allopregnene epoxide, a sapogenin side chain such as A-dehydrotigogenin acylate epoxide, A -dehydrotigogenin acetate epoxide,and the like.

In preparing these epoxides of A -cyclopentanopolyhydrophenanthrenecompounds, utilized as starting materials in our procedure, Weordinarily start with the corresponding Algal)cyclopentanopolyhydrophenanthrene compound, certain of which, such asergosterol D and 3-acyloxy derivatives thereof are described in theprior art. Other A' -cyclopentanopolyhydrophenanthrene compounds can beprepared, starting with readilyavailable A-cyclopentanopolyhydrophenanthrene compounds such as cholesterol, bytreating said A -cyclopentanopolyhydrophenanthrene compound (Compound 6hereinbelow) with N-bromosuccinimide, reacting the resulting A-7-bromo-cyclopentanopolyhydrophenanthrene compound (Compound 7) with atertiary amine to form 3 the corresponding A-cyclopentanopolyhydrophenantherene compound (Compound 8), reacting thiscompound with hydrogen in the presence of Raney nickel catalyst therebyselectively reducing the unsaturated linkage attached to the carbon atomin the 5-position to form the corresponding A'cyclopentanopolyhydrophenanthrene compound (Compound 9) and bringingsaid A"- cyclopentanopolyhydrophenanthrene compound into intimatecontact with a solution of mercuric acetate in acetic acid therebyproducing the corresponding A -cyclopentanopolyhydrophenanthrenecompound (Compound The reactions indicated hereinabove may be chemicallyrepresented (insofar as rings B and C are concerned) as follows:

i/ \l Bromosuccimmlde Mercuric acetate Compound 10 The A'-cyclopentanopolyhydrophenanthrene compound thus obtained is thenconverted to the corresponding epoxide by reaction with perbenzoic acidthus forming the corresponding A-9,11-epoxy-cyclopentanopolyhydrophenanthrene compound (Compound 1hereinbelow) or the corresponding A-7,8-epoxy-cyclopentanopolyhydrophenanthrene (Compound 2). This reactionmay be chemically represented (with respect to the chemical changesoccurring in rings B and C) as follows:

l u p l I 3 1 2 2 Compoundl V l v acid Compound 10 /0 Compound 2 Incarrying out our novel process, the epoxide of the A1-cyclopentanopolyhydrophenanthrene compound,

4 utilized as starting material therein, is reacted with a hydrogenhalide such as hydrogen chloride, hydrogen bromide, and the like, underanhydrous conditions, to produce the corresponding A-7,ll-dihalo-cyclopentanopolyhydrophenanthrene compound. The reactionbetween the epoxide of the A -cyclopentanopolyhydrophenanthrene startingmaterial and the hydrogen halide is ordinarily conducted by bringing thereactants together in a liquid medium inert under the reactionconditions, as, for example, in a hydrocarbon solvent such as benzene ortoluene, in an ethereal solvent such as diethyl ether, in a chlorinatedhydrocarbon solvent such as chloroform, in a ketone such as acetone andthe like. As to the hydrogen halide, it is ordinarily preferred toutilize dry hydrogen chloride, and to conduct the reaction utilizingcold chloroform as the reaction solvent. An excess of hydrogen halide ispreferably used in order to insure complete formation of the dihalocompound. The reaction is preferably carried out in the cold (i.e., at atemperatnre of about 0 C.), but temperatures up to about 25 C. can beemployed, if desired.

The reaction between the epoxide of the A-cyclopentanopolyhydrophenanthrene compound and the hydrogen halideresults in the formation of the corresponding A 7,11dihalo-cyclopentanopolyhydrophenanthrene compound such as: A-7,ll-dihalo-ergostadiene, A -3-acyloxy-7,1l-dihalo-ergostadiene, A-3-acetoxy 7,1l-dichloro-ergostadiene, A -7,l1-dihalo-cholestene, A 3acyloxy 7,11 dihalocholstene, A 3 acetoxy 7,l l-dichloro-cholestene, A-3-acyloxy- 7,11 dihalo-stigmastadiene, A 3 acetoxy 7,11dichloro-stigrnastadiene, A 3 acyloxy-7,11-dihalocholenic acid, A-3-8.C6t0XY-7,1LiliChIOI'O-ChOlfiniC acid, A-3-acyloXy-7,ll-dihalo-bisnorallocholenic acid, A3-acetoxy-7,1l-dichloro bisnorallocholenic acid, M -3- acyloxy7,1l-dihalo-20-keto-allopregnene, A -3-acetoxy-7, ll-dichloro-20-keto-allopregene, A -7,1l-dihalodehydrotigogenin acylate,A -7,1l-dichloro-dehydrotigogenin acetate, and the like.

The A8(9) 7,11-dihalo-cyclopentanopolyhydrophenanthrene compound is thenreacted with an aqueous solution of a metal salt, characterized ashaving a cation which forms water-insoluble halides and an anion whichis nonreactive With the steroid compound, such as aqueous silvernitrate, aqueous silver oxide, aqueous mercnrous nitrate, and the like,thereby forming the corresponding11-keto-cyclopentanopolyhydrophenanthrene compound having a double bondconnecting the carbon atom in the 8-position with a carbon atom adjacentthereto and gamma with respect to the ll-keto substituent. In conductingthis reaction, the A -7,1l-dihalo-cyclopentanopolyhydrophenanthrenecompound is ordinarily dissolved in a Water-miscible organic solventsuch as acetone, and the resulting solution is mixed with an aqueoussolution of the metal salt, whereupon an immediate reaction takes placeas is evidenced by the copious precipitation of the metal halide. Theresulting mixture is then diluted with an additional quantity of thewater-miscible organic solvent and the resulting mixture is allowed toremain at room temperature for about two hours in order to insurecompletion of the reaction. The precipitated metal halide is separatedfrom the reaction mixture by filtration, and the fl-unsaturated-ll-keto-cyclopentanopolyhydrophenanthrene compound formedin the reaction is recovered from the filtered reaction solution. Thisis conveniently effected by diluting this solution with water, whereuponsaid fi,y-unsaturated-ll-keto-cyclopentanopolyhydrophenanthrene compoundprecipitates and is recovered by filtration.

The 11-keto-cyclopentanopolyhydrophenanthrene compounds, obtained withthe foregoing procedure are ,Byy-unsaturated with respectto the '1l-keto substituent (that is they have a double bond connecting the8-carbon atom with a carbon atom adjacent thereto and gamma with respectto the ll-keto substituent), and include A y -llketo-ergostadiene, A-lI-keto-ergostadiene, M 3 acyloxy-ll-keto-ergostadiene, A-fi-acyloxy-llketo-ergostadiene, A" -3-actoxy-ll-keto-ergostadiene, A3-acetoxy-1l-keto-ergostadiene, A' -l1-ketocholestene, A4l-keto-cholestene, A -3-acyl0xy-1lketo cholestene, A-3-acyloxy-1l-keto-cholestene, A 3-acetoxy-11-ketocholestene, A-3-acetoxy-11- keto-cholestene, A -3-acyloxy-1l-keto-stigmastadiene, A-3-acyloxy-ll-keto-stigmastadieue, A' G-acetoxy-l l-keto-stigmastadiene,A -fi-acetoxy-l1-keto stigmastadiene, A -3-acyloxy-1l-keto-cholenicacid, A -3-acetoxy-1-l-keto-cholenic acid, A -3acyloxyll-keto-cholenicacid, A -3-acetoxy-1l-keto-cholenic acid, 13 3acyloxy-l'l-keto-bisnorallocholenic-acid, A-3-acyloxy-1l-keto-bisnorallocholenic acid, A -3-acetoxy'll-keto-bisnorallocholenic acid, A-3-acetoxyll-keto-bisnorallocholenic acid, A-3-acyloxy-1l,20-diketo-allopregnene, A-3-acyloxy-l1,20-diketo-allopregnene, A-3-acetoxy-11,20-diketo-allopregnene, A 3-acetoxy-l1,20-diketo-allopregnene, A -1 l-keto-dehydrotigogenin-acylate,A 4 l-keto-dehydrotigogenin acylate, A' 11 ketodehydrotigogenic-acetate, A -llketo-dehydrotigogenin-acetate, and thelike.

These fi -unsaturated-ll-keto-cyclopentanopolyhydrophenanthrenecompounds are then converted to the desired A-11-keto-cyclopentanopolyhydrophenanthrene compound by treating theformer with a base such as an alkali metal hydroxide, an alkaline earthmetal hydroxide, ammonium hydroxide, an equeous solution of an organicbase such as pyridine, and the like. It is ordinarily preferred todissolve the alkali metal hydroxide and the 3,7- unsaturated11-keto-cyclopentanopolyhydrophenanthrene compound in alcohol, and toallow the resulting alcoholic solution to stand at room temperature foran extended period of time, whereupon the N-unsaturated linkageconnecting the 8-carbon atom and the carbon atom in the 7 or 14 positionrearranges to join the carbon atoms in the 8 and 9-positions. There isthus obtained the desired A 1l-keto-cyclopentanopolyhydrophenanthrenecompound such as A309) -1l-keto-ergostadiene, A -3- hydroxy-ll-keto-ergostadiene, A -3-hydroxy-1 l-ketostigmastadiene, A-3-hydroxy-1l-keto-cholenic acid, A-3-hydroxy-11,20-diketo-allopregnene, A -11-ketodehydrotigogenin, andthe like.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 One-half gram of ergosteryl D-acetate epoxide (i.e., theepoxide of A -3-acetoxy-ergostatriene) was dissolved in 25 cc. ofchloroform, the solution was cooled to about C., and dry hydrogenchloride was bubbled through the solution for a period of approximately30 minutes. The reaction solution was distilled under reduced pressurethereby removing the excess hydrogen chloride and chloroform, and theresidual oil was crystallized from petroleum ether. The crystallinematerial was recovered by filtration, washed with petroleum ether anddried to give substantially pure A -3-acetoxy-7,11-dichloro-ergostadiene; M.P. l25130 C.,dec. Analysis- Calcd for C H Cl OC, 70.75; H, 9.12; CI, 13.91. Found: C, 70.33; H, 9.18; Cl, 13.96.

Example 2 Two-tenths of a gram of A-3-acetoxy-7,ll-dichloro-ergostadiene was dissolved in 20 cc. ofacetone, and to the solution was added, with stirring, cc. of a 0.1 Naqueous solution of silver nitrate. An immediated reaction took placeaccompanied by copious precipitation of silver chloride. The reactionmixture was diluted with an additional 20 cc. of acetone, and theresulting mixture was allowed to stand at room temperature for a periodof about 2 hours. The reaction slurry was then filtered,

thereby removing the silver chloride, and the insoluble material waswashed with acetone. Several volumes of water were added to the filteredsolution, whereupon a crystalline production precipitated. Thiscrystalline product was recovered by filtration, washed with water anddried to give crude A -3-acetoxy-1l-keto ergostadiene having a doublebond connecting the 8-carbon atom with the carbon atom in the 7- or14-position of the molecule.

The crude material was purified by slurrying with a mixture of ethylacetate and petroleum ether, whereupon substantially all of the productdissolved; the resulting solution was the filtered and the filteredsolution was evaporated to dryness; the'residual material wasrecrystallized from ether, and then from methanol to give substantiallypure A -3-acetoxy-l l-keto-ergostadiene having a double bond connectingthe carbon atom in the 8-position with that in the 7- or 14-position ofthe molecule; MP. 178- 181 C. Analysis.-Calcd for G l-1 0 C, 79.25; H.10.20. Found: C, 79.17; H, 10.15.

Example 3 Eleven milligrams of the A -3-acetoxy-1l-keto-ergostadienehaving a double bond connecting the carbon atom in the 8-position withthe carbon atom in the 7- or 14- position of the molecule (prepared asdescribed in Example 2 hereinabove) were dissolved in methanol and 50milligrams of potassium hydroxide was added to the resulting solution.The resulting solution was allowed to stand for about 15 hours at atemperature of about 25 C. The reaction solution was then worked up asfollows: The potassium hydroxide was neutralized by addition of aceticacid. Water was added and the methanol was removed by distillation. Thewater-insoluble precipitate was collected on a filter and recrystallizedrepeatedly from methanol to give substantially pure A3-hydroxy-l'l-keto-ergostadiene which was identified byspectrophotometric analysis:

gigu'tane These 11 11 keto-cyclopentanopolyhydrophenanthrene compoundssuch as A -3-hydroxy-1l-ketoergostadiene, A3-hydroxy-ll-keto-stigmastadiene, A -3-hydroxy-1l-keto-cholenic acid, A-3-hydroxy- 11,20 diketo allopregnene, A?) -11 keto-dehydrotigo genin,3-acetates thereof, and the like, can be reduced with metallic reducingagents, such as lithium in liquid ammonia, or zinc dust in ethanolichydrochloric acid solution to form the corresponding nuclearly saturatedll-keto-steroid. For example twenty grams of A-3-hydroxy-1l-keto-ergostadiene or its 3-acetate in ml. dry ethyl etherwere added with stirring to 2 liters of liquid ammonia. Twelve grams offreshly cut lithium were then added, and the reaction mixture wasstirred at reflux temperature for a period of about six hours. Onehundred and fifty milliliters of absolute ethanol was added to thereaction mixture over a period of 35 minutes. After all the ethanol hadbeen added, the blue color due to dissolved lithium disappeared. Fortymilliliters of water was added to the resulting mixture, and the ammoniawas allowed to evaporate overnight through a mercury trap. The residualethereal layer was separated, washed With water, dried over sodiumsulfate, and the ether was evaporated therefrom in vacuo, leaving acrude white solid.

This solid was dissolved in ether, chromatographed over alumina and thealumina adsorbate was eluted, first with ether and then with a solutionof 1% methanol in ether. From the ether eluate there was obtainedcrystalline A -ergostene-3/3-ol-1-1-one, M.P. 166-168" C., (a) -=+31(CHCl Calculated for C H O Theory: C, 81.2; H, 11.20. Found: C, 81.10;H, 10.91.

The conversion of these nuclearly unsaturated ll-ketosteroids, such as A-ergostene-3B-ol-1l-one to allopregnane-3fl-ol-1l,20-dione acetate isdisclosed in J.A.C.S. 73, 2396 (May 1951); J.A.C.S. 73, 4052 (August1951) use the latter compound to prepareallopregnane-3fi,17a,2ltriol-1l,20-dione 21-.acetate; the conversion ofthe lastnamed compound to cortisone acetate is set forth in Nature 168,page 28 (July 1951).

Various changes and modifications may be made in carryingout the presentinvention without departing from the spirit and scope thereof. Insofaras these changes and modifications are within the purview of the annexedclaims, they are to be considered as part of our invention.

We claim: 7

1. The process which comprises reacting ergosteryl D- acetate epoxidewith an excess of dry hydrogen chloride in chloroform solution at atemperature below about 25 C. to form A-3-acetoxy-7,1l-dichloro-ergostadiene, reacting this compound insolution in acetone with an aqueous solution of silver nitrate toproduce a A 3- acetoxy-l l-keto-ergostadiene compound having a doublebond connecting the carbon atom in the 8-position with a carbon atomadjacent thereto and gamma with respect to the ll-keto-substituent, andreacting the latter compound with potassium hydroxide in methanol atapproximately room temperature to form A -3-hydroxy-11- ketoergostadiene.

2. The process which comprises reacting an excess of a hydrogen halideunder anhydrous conditions and at a temperature below about 25 C. withan epoxide of a A -cyclopentanopolyhydrophenanthrene compound having a-17 side chain selected from the group consisting of sterol side chain,bile acid side chain, degraded bile acid side chain, 17-acetyl sidechain, and sapogenin side chain, thereby forming the corresponding M-7,11- dihalo-cyclopentanopolyhydrophenanthrene compound.

3. The process which comprisesreacting ergosteryl D- acetate epoxideWith an excess of dry hydrogen chloride in chloroform solution .at atemperature below about 25 C; to produce A-3-acetoxy-7,1l-dichloro-ergostadiene.

4. The process which comprises reacting a A -7,1ldihalocyclopentanopolyhydrophenanthrene compound having a C-17 side chainselected from the group consisting of sterol side chain, bile acid sidechain, degraded bile acid side chain, 17-acetyl side chain, andsapogenin side chain in solution in a water-miscible organic solventwith an aqueous solution of a metal salt, characterized as having acation which forms water-insoluble-halides; thereby forming thecorresponding 1l-keto-cyclopentano polyhydrophenanthrene compoundhavinga double bond connecting the carbon atom in the 8-position with-acarbon atom adjacent thereto and gamma with respect to the 11- ketosubstituent.

- 5. The process which comprises reacting A -3-acetoxy-7,1l-dichloro-ergostadiene in solution in acetone with aqueoussilver nitrate to produce a A -3-acetoxy-l lketo-erg'ostadiene compound,having a double bondconmeeting the carbon atom in the 8-position with acarbon atom adjacent thereto and gamma with respect to the 1-1- ketosubstituent.

6. The process which comprises reacting anll-ketocyclopentanopolyhydrophenauthrene compound having a C-17 sidechain selected from the group consisting of sterol side chain, bile acidside chain, degraded bile acid side chain, 17-acetylside chain,rand,sapogenin side chain, and having a double bond connecting the carbonatom in the' 8-position with a carbon atom adjacent thereto and gammawith respect to the ll-keto substituent,

with a base at approximately room temperature to form the correspondingA -l1-keto-cyclopentanopolyhydroa phenanthrene compound.

7. The process which comprises reacting a A 3-acetoxy-ll-keto-ergostadiene having a double bond connecting the carbonatom in the 8-position with a carbon atom adjacent thereto and gammawith respect to the 11- keto substituent, with potassium hydroxide inmethanol at approximately room temperature to produce A 3 -hydroxy- 1l-keto-ergostadiene.

8. A -3-acetoxy-l l-keto-ergostadiene.

References Cited in the file of this patent UNITED STATES PATENTSLaubach et a1 Aug. 6, 1957 Chemerda et a1 June 3, 1958

8. $8(14),22-3-ACETOXY-11-KETO-ERGOSTADIENE.